Follicular Variant of Papillary Thyroid Carcinoma

Vania Nosé, M.D., Ph.D. Director of Anatomic and Molecular Pathology Massachusetts General Hospital Professor of Pathology, Harvard Medical School

Follicular Thyroid Lesions and Neoplasms – Hyperplasic nodule – Follicular adenoma – Adenomatous nodule – Macrofollicular, microfollicular, oncocytic – Follicular thyroid carcinoma – Papillary thyroid carcinoma, follicular variant – Non-invasive follicular thyroid neoplasm with papillary-like nuclei (NIFTP)

Follicular Variant of Papillary Thyroid Carcinoma: What is new?

NIFTP

Follicular Variant of PTC • Clinical –Same age and gender as conventional –Slightly different prognosis • Lower lymph node metastases • 10-year: 90% (FV) vs. 96% (conventional)

Follicular Variant of PTC • Histologic features – Pure follicular architecture – Papillary carcinoma nuclei • RARE to absent intranuclear pseudoinlcusions – If present, r/o classical type, r/o oncocytic (Hürthle cell) neoplasm

– Irregular nuclear membranes – Some encapsulated • +/- invasion

Follicular Variant of PTC • Histologic features – Encapsulated • Without capsular invasion • With capsular invasion • With lymphovascular invasion

– Well-circumscribed – Invasive • With fibrosis

Follicular variant PTC

Follicular variant PTC

Follicular variant PTC

Special Studies in Papillary Carcinoma • Immunohistochemistry: HBME1 • Molecular mutations

BRAF mutations • Tumors – Melanoma – Cholangiocarcinoma – Papillary thyroid carcinomas – etc

• Mutation – Activating mutation in exon 15 – Valine > glutamate (V600E) – Simulates phosphorylation in activation site

BRAF in Papillary Carcinoma 50% 40% 30% 20% 10% 0% FVPTCa

PTCa

FCa

FA

RET-PTC Translocations • Tumors – Papillary thyroid carcinomas

• Translocation – Different partner genes • ELE1 and H4 most common

– Constitutively activated tyrosine kinase – Fusion protein translocation to cytoplasm

RET/PTC in Papillary Carcinoma 40%

30%

20%

10%

0% FVPTCa

PTCa

FCa

FA

Mutations in FVPTC • RAS (N-K-H) • PAX8-PPARγ • Integrated genomic characterization of papillary thyroid carcinoma – Cell. 2014 Oct 23;159(3):676-90.

• Implications for TCGA genomic characterization of papillary thyroid carcinoma: does follicular variant of papillary thyroid carcinoma exist? – Asa SL, Giordano TJ, LiVolsi VA; Thyroid. 2015 Jan;25(1):1-2.

Mutations in FVPTC

McFadden DG, et al.; J Clin Endocrinol Metab. 2014 Nov;99(11):E2457-62.

Follicular Variant • Architecture: –Encapsulated –Well-circumscribed –Invasive

Follicular Variant • Subtle histologic features – Low power assessment • Nuclear atypia at 4X (different from background) • Clustered atypia • Nuclear features more pronounced under capsule

– Architecture • Perifollicular fibrosis • Thick colloid • Abortive papillae

Follicular variant PTC

Follicular variant PTC

Follicular variant PTC

Follicular Variant of PTC • Subtle histologic features – Nuclei • Flattened or pushed in side • Irregular contours • Small peripheral nucleoli

Follicular variant PTC

Nuclear clearing

Crowded Overlapping

Nuclear grooves

Papillary Thyroid Carcinoma

Follicular variant PTC

Normal follicles

Challenging Follicular Variants • Macrofollicular lesions • Lesions with scattered nuclear features: sprinkling sign

Follicular variant PTC

Follicular variant PTC

Follicular variant PTC

Follicular variant PTC

Follicular variant PTC

Pitfalls in FVPTC • Things to avoid – Exclude reactive areas • FNA area • Degenerative changes

– Exclude microscopic papillary carcinoma within a nodule – Nuclear features that are just too good – Frozen section

Problem Areas in Follicular Variant • Well-circumscribed tumors? • Encapsulated tumors? • Lesions with scattered nuclear features – Diagnosis? – Size of tumor?

Changes… • Recent publication on this fastest growing subtype of the most common endocrine cancer

• Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of encapsulated papillary thyroid carcinoma follicular variant. Ganly I et al.; Hum Pathol. 2015 Feb 4.

• Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma. McFadden DG, et al.; J Clin Endocrinol Metab. 2014 Nov;99(11):E2457-62.

• Molecular alterations in partially-encapsulated or well-circumscribed follicular variant of papillary thyroid carcinoma. Howitt BE, et al. ; Thyroid. 2013 Oct;23(10):1256-62.

International Consortium: Working Group for Reclassification of the Encapsulated Follicular Variant of Papillary Thyroid Carcinoma

• Pathologists and a few clinicians (surgeons, endocrinologists) • Over 200 cases of invasive carcinomas • Non-invasive, encapsulated neoplasms • Nuclear scoring • Classification • New name?? – Meeting USCAP, Boston, 2015 (March 20-21)

May 25, 2015: • Non-invasive follicular thyroid neoplasm with papillary-like nuclei • Aka NIFTP (non-invasive follicular tumor, papillary-like) • Would define the tumor to be biologically inert, regardless of degree of nuclear membrane irregularities • Definition still in evolution • Publication should be submitted shortly

Implications of NIFTP • Reduced diagnosis of follicular variant of papillary thyroid carcinoma • Reduced over-treatment of indolent thyroid tumors • Reduced need for consultation due to increased reproducibility of morphological features – and reduced use of immunohistochemistry • Update to Bethesda FNA criteria

JAMA Oncology, published on line, April 14, 2016

Paper • Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. • JAMA Oncol. 2016 Aug 1;2(8):1023-9. Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, ElNaggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA.

Follicular variant of PTC • Recognized in the mid-1970s • Two types follicular variant of PTC: -Encapsulated /circumscribed (EFVPTC) -Infiltrative • EFVPTC constitutes 10%-20% of all thyroid cancers diagnosed in Europe and North America.

Diagnostic criteria for EFVPTC •

•

•

Major features: – Encapsulation or clear demarcation – Follicular growth pattern – Nuclear features of PTC Minor features: – Dark colloid – Irregulare shaped follicles – Intratumor fibrosis – Sprinkling sign – Multinucleated giant cells – Follicles cleft from the stroma Exclusion features – True papillae (>1%) – Psammoma bodies – Infiltrative border – Tumor necrosis – High mitotic activity (>3 /10 HPF) – Cell/morphology characteristic of other variants of PTC

Endocrine Pathology Society Working Group Conclusion • Nomenclature revision needed • Old term: Encapsulated follicular variant of papillary thyroid carcinoma • New name: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NFITP)

• • • •

NIFTP requires no additional surgery Likely to drive more lobectomies Submission will be similar to solitary adenomas Diagnosis driven by absence of capsular/vascular invasion • Invasion removes it from NIFTP category and becomes invasive EFVPTC

The “capsule” • NIFTP does not require a capsule • Requires tumor to be well-circumscribed • For NIFTP, the “capsule” becomes the tumor:non-tumor interface • The interface should be “adequately sampled”

Case Presentation 53 year-old male with multinodular goiter with prominent nodules

Ultrasound 2.3 cm nodule #2

0.9 cm nodule #1

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY

HARVARD MEDICAL SCHOOL

Histology

Nodule #1 • Infiltrative • Follicular architecture • Nuclear features of PTC

Nodule #2 • Well-circumscribed • Follicular architecture • Nuclear features of PTC

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY

HARVARD MEDICAL SCHOOL

Histology

Nodule #1 • Follicular architecture • Nuclear features of PTC

Nodule #2 • Follicular architecture • Nuclear features of PTC

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY

Nodule #1 • Positive

HARVARD MEDICAL SCHOOL

HBME-1 Nodule #2 • Positive

Diagnosis Multifocal Papillary Thyroid Carcinoma, Follicular Variant

?

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY

Our Patient

Nodule #1 • • • •

PTC nuclei Follicular architecture INFILTRATIVE GROWTH BRAF positive

• Just like classical-type PTC

HARVARD MEDICAL SCHOOL

Nodule #2 • PTC nuclei • Follicular architecture • NON-INVASIVE, CIRCUMSCRIBED

• BRAF negative

• Just like follicular adenoma/carcinoma

PTC, Follicular variant Infiltrative Follicular Pattern • BRAF-like • Similar to classical-type molecularly and in behavior

Encapsulated Follicular Pattern • RAS-like • Similar to follicular adenoma/carcinoma molecularly and in behavior

MASSACHUSETTS GENERAL HOSPITAL

HARVARD MEDICAL SCHOOL

PATHOLOGY

Lets suppose….. these nodules were in separate patients….

HARVARD MEDICAL SCHOOL

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY

Patient #2

Patient #1 • Morphology:

• Morphology: – PTC nuclei – Follicular architecture – Confined growth

– PTC nuclei – Follicular architecture – Infiltrative growth

• Molecular profile: BRAF positive (similar to classical-type)

•

Diagnosis: Papillary thyroid carcinoma, follicular variant, invasive • Behavior prediction: nodal spread (similar to classical type!) • Treatment: Total lobectomy plus radioiodide treatment +/- lymph node dissection

• Molecular profile: BRAF negative RAS positive (similar to follicular adenoma)

• • • • • • •

Diagnosis: NIFT Behavior prediction: indolent Treatment: Lobectomy alone NO radioiodine therapy! NO additional surgery! NO additional cost! NO psychological trauma!!

Molecular Pathways in Thyroid Papillary Carcinogenesis

29-77%

Tall-cell, columnar cell, and hobnail variants PTC have a high prevalence of BRAF mutation

0-21%

Follicular Variant of PTC have a low prevalence of BRAF, higher RAS mutation

13-43%

Classical Variant of PTC have a low prevalence of BRAF, higher RET-PTC

Progress in Identifying Driver Mutations in Thyroid Cancer 1990

2000

2005

20%

30%

70%

RAS RET/PTC TP53 TRK PTEN b-catenin

RAS RET/PTC TP53 TRK PTEN b-catenin PAX8/PPARg BRAF PIK3CA BRAF/AKAP9

RAS RET/PTC

Progress in Identifying Driver Mutations in Thyroid Cancer Reduced “Dark Matter” of unknown driver mutations

1990

2000

2005

2014

20%

30%

70%

>90%

RAS RET/PTC TP53 TRK PTEN b-catenin

RAS RET/PTC TP53 TRK PTEN b-catenin PAX8/PPARg BRAF PIK3CA BRAF/AKAP9

RAS RET/PTC

RAS RET/PTC TP53 TRK PTEN b-catenin PAX8/PPARg BRAF PIK3CA BRAF/AKAP9

AKT1 STRN/ALK ETV6/NTRK3 EIF1AX

Common Mutations in Types of Thyroid Cancer PTC, classical and tall cell BRAF V600E

PTC, follicular variant

Follicular Carcinoma

+++

Poorlydifferentiated carcinoma

Anaplastic carcinoma

+

+

Follicular adenoma

BRAF K601E

+++

+

NRAS

+++

++

HRAS

++

+

+

++

+

++

PTEN

+

++

TSHR

+

++

KRAS

+

+ +

+

GNAS RET/PTC

++

++ +++

PAX8PPARG

+

ALK FUSIONS

+

+

BRAF FUSIONS

+

+

ETV6/NTRK

++

NTRK FUSIONS

++

+++ ++

++